Tau-mediated NMDA receptor impairment underlies dysfunction of a selectively vulnerable network in a mouse model of frontotemporal dementia.

Frontotemporal dementia (FTD) is a neurodegenerative behavioral disorder that selectively affects the salience network, including the ventral striatum and insula. Tau mutations cause FTD, but how mutant tau impairs the salience network is unknown. Here, we address this question using a mouse model expressing the entire human tau gene with an FTD-associated mutation (V337M). Mutant, but not wild-type, human tau transgenic mice had aging-dependent repetitive and disinhibited behaviors, with synaptic deficits selectively in the ventral striatum and insula. There, mutant tau depleted PSD-95, resulting in smaller postsynaptic densities and impaired synaptic localization of NMDA receptors (NMDARs). In the ventral striatum, decreased NMDAR-mediated transmission reduced striatal neuron firing. Pharmacologically enhancing NMDAR function with the NMDAR co-agonist cycloserine reversed electrophysiological and behavioral deficits. These results indicate that NMDAR hypofunction critically contributes to FTD-associated behavioral and electrophysiological alterations and that this process can be therapeutically targeted by a Food and Drug Administration-approved drug.

Coactivation of M(1) muscarinic and alpha1 adrenergic receptors stimulates extracellular signal-regulated protein kinase and induces long-term depression at CA3-CA1 synapses in rat hippocampus.

Intact cholinergic innervation from the medial septum and noradrenergic innervation from the locus ceruleus are required for hippocampal-dependent learning and memory. However, much remains unclear about the precise roles of acetylcholine (ACh) and norepinephrine (NE) in hippocampal function, particularly in terms of how interactions between these two transmitter systems might play an important role in synaptic plasticity. Previously, we reported that activation of either muscarinic M(1) or adrenergic alpha1 receptors induces activity- and NMDA receptor-dependent long-term depression (LTD) at CA3-CA1 synapses in acute hippocampal slices, referred to as muscarinic LTD (mLTD) and norepinephrine LTD (NE LTD), respectively. In this study, we tested the hypothesis that mLTD and NE LTD are independent forms of LTD, yet require activation of a common Galphaq-coupled signaling pathway for their induction, and investigated the net effect of coactivation of M(1) and alpha1 receptors on the magnitude of LTD induced. We find that neither mLTD nor NE LTD requires phospholipase C activation, but both plasticities are prevented by inhibiting the Src kinase family and extracellular signal-regulated protein kinase (ERK) activation. Interestingly, LTD can be induced when M(1) and alpha1 agonists are coapplied at concentrations too low to induce LTD when applied separately, via a summed increase in ERK activation. Thus, because ACh and NE levels in vivo covary, especially during periods of memory encoding and consolidation, cooperative signaling through M(1) and alpha1 receptors could function to induce long-term changes in synaptic function important for cognition.

Coexistence of muscarinic long-term depression with electrically induced long-term potentiation and depression at CA3-CA1 synapses.

Our laboratory recently characterized a form of long-term depression (LTD) at CA3-CA1 synapses mediated by M1 muscarinic receptors (mAChRs), termed muscarinic LTD (mLTD). mLTD is both activity and NMDAR dependent, characteristics shared by forms of synaptic plasticity thought to be relevant to learning and memory, including long-term potentiation (LTP) induced by high-frequency stimulation (HFS-LTP) and long-term depression induced by low-frequency stimulation (LFS-LTD). However, it remains unclear whether mLTD can occur sequentially with these electrically induced forms of hippocampal plasticity or whether mLTD might interact with them. The first goal of this study was to examine the interplay of mLTD and HFS-LTP. We report that mLTD expression does not alter subsequent induction of HFS-LTP and, further, at synapses expressing HFS-LTP, mLTD can mediate a novel form of depotentiation. The second goal was to determine whether mLTD would alter LFS-LTD induction and/or expression. Although we show that mLTD is occluded by saturation of LFS-LTD, suggesting mechanistic similarity between these two plasticities, saturation of mLTD does not occlude LFS-LTD. Surprisingly, however, the LFS-LTD that follows cholinergic receptor activation is NMDAR independent, indicating that application of muscarinic agonist induces a change in the induction mechanism required for LFS-LTD. These data demonstrate that mLTD can coexist with electrically induced forms of synaptic plasticity and support the hypothesis that mLTD is one of the mechanisms by which the cholinergic system modulates hippocampal function.

Sympathetic sprouting drives hippocampal cholinergic reinnervation that prevents loss of a muscarinic receptor-dependent long-term depression at CA3-CA1 synapses.

Degeneration of septohippocampal cholinergic neurons results in memory deficits attributable to loss of cholinergic modulation of hippocampal synaptic circuits. A remarkable consequence of cholinergic degeneration is the sprouting of noradrenergic sympathetic fibers from the superior cervical ganglia into hippocampus. The functional impact of sympathetic ingrowth on synaptic physiology has never been investigated. Here, we report that, at CA3-CA1 synapses, a Hebbian form of long-term depression (LTD) induced by muscarinic M1 receptor activation (mLTD) is lost after medial septal lesion. Unexpectedly, expression of mLTD is rescued by sympathetic sprouting. These effects are specific because LTP and other forms of LTD are unaffected. The rescue of mLTD expression is coupled temporally with the reappearance of cholinergic fibers in hippocampus, as assessed by the immunostaining of fibers for VAChT (vesicular acetylcholine transporter). Both the cholinergic reinnervation and mLTD rescue are prevented by bilateral superior cervical ganglionectomy, which also prevents the noradrenergic sympathetic sprouting. The new cholinergic fibers likely originate from the superior cervical ganglia because unilateral ganglionectomy, performed when cholinergic reinnervation is well established, removes the reinnervation on the ipsilateral side. Thus, the temporal coupling of the cholinergic reinnervation with mLTD rescue, together with the absence of reinnervation and mLTD expression after ganglionectomy, demonstrate that the autonomic-driven cholinergic reinnervation is essential for maintaining mLTD after central cholinergic cell death. We have discovered a novel phenomenon whereby the autonomic and central nervous systems experience structural rearrangement to replace lost cholinergic innervation in hippocampus, with the consequence of preserving a form of LTD that would otherwise be lost as a result of cholinergic degeneration.